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Compartmentalized glycogenolysis regulates lung cancer transcription
Author(s) -
Young Lyndsay E.A.,
Sun Ramon,
Emanuelle Shane,
Zhou Zhengqiu,
FillmoreBrainson Christine,
Gentry Matthew
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.652.25
Subject(s) - glycogenolysis , glycogen , epigenetics , biology , glycogen synthase , acetylation , histone , glycolysis , microbiology and biotechnology , biochemistry , metabolism , gene
The role of cellular metabolites in the direct control of epigenetic modifications is an emerging and rapidly evolving field. Herein, we identify a key function for nuclear glycogen in epigenetic regulation through compartmentalized acetyl‐CoA production and histone acetylation. In this study, we report glycogen accumulation in the nucleus of human non‐small cell lung cancer (NSCLC) specimens. To study this striking phenotype, we developed an innovative assay combining high‐purity sub‐cellular organelle isolation and stable isotope tracer technology to define the origin and metabolic fate of nuclear glycogen. We demonstrate that the nucleus is capable of carrying out glycogen synthesis, glycogenolysis and glycolysis, and both glycogen synthesis and glycolysis pathways require glucose‐6‐phosphate as the substrate. Nuclear glycogenolysis is dependent on ubiquitination and translocation of glycogen phosphorylase (GP) into the nucleus by malin, an E3 ubiquitin ligase. GP translocation is required for nuclear glycogen degradation and subsequent glycolysis to generate substrates for histone acetylation. Inhibition of nuclear glycogenolysis as a result of malin suppression is the cause of NSCLC nuclear glycogen accumulation. Re‐introduction of malin in model NSCLC cell lines restores nuclear glycogenolysis, results in increased histone acetylation, and delays cancer cell growth in vivo . This study uncovers a previously unknown foundational role for glycogen metabolism in the nucleus and elucidates another mechanism by which cellular metabolites control epigenetic regulation. Support or Funding Information The study was supported by the National Institute of Neurological Disorders and Stroke (grant ID: R01 NS070899‐06, P01 NS097197‐01), National Science Foundation (Grant ID: MCB‐1817414) and by the University of Kentucky Center for Cancer and Metabolism, National Institute of general medical sciences COBRE program (grant ID: P20 GM121327). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .